?Bacteria produce ?-lactamase enzyme which split the ?- lactam ring and render the antibiotic ineffective.The enzyme is under plasmid control in Gram+ves, and chromosomally controlled in many Gram-ves .The absence of some penicillin receptors (PBPs) due to chromosomal mutation.?Failure of the ?-lactam drug to activate the autolytic enzymes in the bacterial cell wall.?